The human IL-2 receptor and related cytokine receptor systems are being studied to clarify key components of the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the subsequent T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ralpha, IL-2Rbeta and IL-2Rgamma. Dr. Leonard cloned IL- 2Ralpha as a postdoctoral fellow in 1984, and his group discovered IL- 2Rbeta in 1986 and reported in 1993 that mutation of the IL-2Rgamma chain results in X-linked severe combined immunodeficiency (XSCID) in humans. Since the XSCID phenotype is more severe than that in IL-2 deficient humans and mice, the group predicted and showed that IL-2Rgamma was in fact a common gamma chain shared by the receptors for IL-4 and IL-7, and in the past year, that the IL-9 receptor also shares gamma chain. The shared chain between the IL-4 and IL-13 receptors was shown to be IL-4R rather than gamma chain. Having previously demonstrated that heterodimerization of IL-2Rbeta and gamma chain is required for IL-2 signaling, the group reported in the past year that IL-2Rbeta and gamma chain associate with distinct Janus family tyrosine kinases (Jak1 and Jak3, respectively). Interestingly, a patient with a moderate X-linked combined immunodeficiency (XCID) characterized by diminished IL-2 responses had a single amino acid change in the gamma chain cytoplasmic domain that decreased Jak3 association. It was hypothesized that Jak3 activation is essential for intrathymic maturation and/or selection of T cells and that XSCID results from gamma chain mutations that interfere with cytokine binding to gamma chain and/or the association of gamma chain with Jak3, allowing the hypothesis that inactivating Jak3 mutations would cause autosomal recessive cases of SCID indistinguishable from XSCID. Indeed, a girl with phenotype indistinguishable from XSCID was found to have an autosomal recessive forms SCID resulting from Jak3 deficiency. In the past year, the group has clarified the signaling domains of IL-2Rbeta and gamma chain by mutagenesis, ha reported studies analyzing gamma chain on monocytes and neutrophils, and has further analyzed the role of gamma chain in IL-7 signaling. Major advances have been made in creating a gamma chain knockout mouse, elucidating the critical residues in the IL-2Rbeta cytoplasmic domain required for signaling, and using the yeast two-hybrid system to identify proteins that can interact with gamma chain. Energies have also focused on the development of gene therapy for XSCID. Both retroviral and adeno associated viral constructs have been made, and initial results have been reported for the retroviral approach.